Type III interferon-mediated effector functions of adaptive NK cells involved in control of HCMV infection

III型干扰素介导的适应性NK细胞的效应功能参与控制HCMV感染

• 批准号: 514891263
• 负责人: Professor Dr. Markus G. Uhrberg
• 金额: --
• 依托单位: Institut für Transplantationsdiagnostik und Zelltherapeutika (ITZ)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/514891263?language=en
• 关键词: Type; III; interferon; mediated; effector

Natural killer (NK) cells are part of the first line of defense against acute viral infections. Recently, a novel type of virus-specific NK cell was identified that expands during acute cytomegalovirus (CMV) infection and efficiently mediates antibody-dependent cellular cytotoxicity (ADCC). In contrast to conventional NK cells, adaptive NK cells can persist for many years and thus have the potential to contribute to long-term protection against reinfection or reactivation from latency. A hallmark of these adaptive (also known as memory) NK cells is the expression of the stimulatory receptor NKG2C, which binds to human leucocyte antigen E (HLA-E). Besides the well-defined HLA-E/NKG2C axis, it is presently unclear which other factors control the activation of adaptive NK cells during viral infections. In this regard, we have acquired preliminary data showing that adaptive NK cells are uniquely responsive to type III interferons, i.e. IFN lambda (IFNl) 1-4 due to specific up-regulation of the IFNl receptor (IFNlR). Lambda IFNs are a more recently described class of IFNs with homology to the classic type I IFNs (IFNalpha/beta) but with a more focused mode of action, including front-line immune responses against virus-infected epithelial cells. The responsiveness of adaptive NK cells to IFNl is particularly relevant given the well-described low sensitivity of adaptive NK cells to other key cytokines acting on conventional NK cells, such as IL-12 and IL-18. The results of additional transcriptomic analyses suggest that exposure to IFNl initiates a highly specific virus defense program in adaptive NK cells. In the present project, we would like to thoroughly characterize how type III interferons modulate the effector functions of adaptive NK cells. We would like to understand how IFNl-mediated stimulation synergizes with coactivation via the HLA-E/NKG2C axis and will use transporter associated with antigen processing (TAP)-deficient HLA-E transfectants enabling fine-tuning of HLA-E surface expression by loading defined peptides. Second, we will use transcriptomic, proteomic, and epigenetic analyses to characterize the changes in global expression programs in IFNl-treated primary adaptive NK cells. Third, we plan to analyze how IFNl modulates the function of adaptive NK cells in an in vitro infection model based on coculture of NK cells with human cytomegalovirus (HCMV)-infected mesenchymal stem cells. Finally, we will assess the clinical relevance of IFNl-mediated stimulation of adaptive NK cells by analyzing leukemia patients experiencing HCMV reactivation following chemotherapy and hematopoietic stem cell transplantation (HSCT). Together, the proposed work is expected to lead to a better understanding of type III IFN-mediated regulation of adaptive NK cells during virus infections, which we hope will help to unleash their high translational potential in cellular therapy in the setting of clinical reactivation of HCMV.

自然杀伤细胞是抵御急性病毒感染的第一道防线的一部分。最近，一种新型的病毒特异性NK细胞被发现在急性巨细胞病毒（CMV）感染期间扩增并有效介导抗体依赖性细胞毒性（ADCC）。与传统NK细胞相比，适应性NK细胞可以持续存在多年，因此有可能有助于长期保护，防止再感染或从潜伏期重新激活。这些适应性NK细胞（也称为记忆NK细胞）的一个特征是刺激受体NKG2C的表达，该受体与人类白细胞抗原E （HLA-E）结合。除了明确定义的HLA-E/NKG2C轴外，目前尚不清楚在病毒感染期间还有哪些其他因素控制适应性NK细胞的激活。在这方面，我们已经获得的初步数据表明，适应性NK细胞对III型干扰素，即IFN lambda (IFNl) 1-4有独特的反应，这是由于IFNl受体（IFNlR）的特异性上调。Lambda ifn是最近被描述的一类ifn，与经典的I型ifn （ifn α / β）同源，但具有更集中的作用模式，包括针对病毒感染的上皮细胞的一线免疫反应。鉴于适应性NK细胞对作用于常规NK细胞的其他关键细胞因子（如IL-12和IL-18）的低敏感性，适应性NK细胞对IFNl的反应性特别相关。另外的转录组学分析结果表明，暴露于IFNl会在适应性NK细胞中启动高度特异性的病毒防御程序。在目前的项目中，我们想要彻底表征III型干扰素如何调节适应性NK细胞的效应功能。我们希望了解ifnl介导的刺激如何通过HLA-E/NKG2C轴与共激活协同作用，并将使用与抗原加工相关的转运体（TAP）缺陷的HLA-E转染物，通过加载定义的肽来微调HLA-E表面表达。其次，我们将使用转录组学、蛋白质组学和表观遗传学分析来表征ifnl处理的原代适应性NK细胞中全局表达程序的变化。第三，我们计划在NK细胞与人巨细胞病毒（HCMV）感染的间充质干细胞共培养的体外感染模型中，分析IFNl如何调节适应性NK细胞的功能。最后，我们将通过分析化疗和造血干细胞移植（HSCT）后经历HCMV再激活的白血病患者，评估ifnl介导的适应性NK细胞刺激的临床相关性。总之，这项工作有望导致更好地理解III型ifn介导的适应性NK细胞在病毒感染期间的调节，我们希望这将有助于释放它们在HCMV临床再激活的细胞治疗中的高转化潜力。